chr16-2557811-A-G

Position:

• chr16-2557811-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002613.5(PDPK1):​c.133A>G​(p.Ser45Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000649 in 1,232,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000065 (0 hom.)
• Consequence: PDPK1 NM_002613.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.93

Genes affected

PDPK1 (HGNC:8816): (3-phosphoinositide dependent protein kinase 1) Enables 3-phosphoinositide-dependent protein kinase activity; phospholipase activator activity; and phospholipase binding activity. Involved in several processes, including cell surface receptor signaling pathway; regulation of protein kinase activity; and regulation of signal transduction. Acts upstream of or within intracellular signal transduction. Located in cell projection; cytosol; and plasma membrane. Implicated in prostate cancer. Biomarker of lung non-small cell carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1650163).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDPK1	NM_002613.5	c.133A>G	p.Ser45Gly	missense_variant	2/14	ENST00000342085.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDPK1	ENST00000342085.9	c.133A>G	p.Ser45Gly	missense_variant	2/14	1	NM_002613.5	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000649 AC: 8 AN: 1232210 Hom.: 0 Cov.: 19 AF XY: 0.00000323 AC XY: 2 AN XY: 620154

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000874

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2023

The c.133A>G (p.S45G) alteration is located in exon 2 (coding exon 2) of the PDPK1 gene. This alteration results from a A to G substitution at nucleotide position 133, causing the serine (S) at amino acid position 45 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Uncertain	0.42	T;.;.;T;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.61	T;T;T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	D;D;D;D;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.56	N;N;N;N;N
REVEL	Benign	0.064
Sift	Uncertain	0.0080	D;D;D;D;T
Sift4G	Benign	0.15	T;T;D;T;T
Polyphen		0.0010	B;.;B;.;.
Vest4		0.19
MutPred		0.23		Loss of phosphorylation at S45 (P = 0.0078);Loss of phosphorylation at S45 (P = 0.0078);Loss of phosphorylation at S45 (P = 0.0078);.;.;
MVP		0.78
MPC		1.7
ClinPred		0.18	T
GERP RS		2.8
Varity_R		0.083
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2066528445; hg19: chr16-2607812;